The current proposal is the first to investigate the co-delivery of two promising anticancer agents, suberoylanilide hydroxamic acid (SAHA) and geldanamycin (GA) via original platforms for in vivo evaluations against aggressive breast tumors. This will be accomplished in two phases: (1) a well-designed multifunctional nanoparticle for co-delivery of drugs through caged micelles (training phase) and (2) a multifunctional nanoTRAIN platform (independent phase) to assess the feasibility of the different delivery approaches for combination therapy. The long term goal is to improve chemotherapeutic regressions of aggressive tumors in cancer patients. The objective of the training is to evaluate SAHA and GA in multifunctional caged micelles for combination therapy against a xenograft model of human breast cancer in rodents. The objective of the independent phase is to comparatively evaluate SAHA and GA delivered in nanoTRAINs as the alternative platform for co-delivery of drugs in tumor-bearing rodents. The overall hypothesis is that in vivo co-delivery of SAHA and GA will lead to superior antitumor effects due to greater therapeutic efficacy and lower dose limiting toxicities than individual drugs. The resulting data will be significant by providing in vivo insights into the therapeutic combination of GA and SAHA as well as insights into a new co-delivery concept. NanoTRAINs are important because emerging cancer research into drug combinations has demonstrated that many molecularly targeted drugs can also be exploited to sensitize drug-resistant cancers to standard chemotherapeutics that had previously failed. Therefore, effective cancer treatments would rest not only on a comprehensive biochemical understanding of the cancer cell (to enable the rational design of promising combinations), but also on versatile platforms that would enable for concerted delivery of a variety of drug combinations. The broader impact is that nanoTRAINs may provide simpler co-delivery solutions, in contrast to complicated multifunctional nanoparticles, for bringing promising combination treatments more rapidly to the clinics, and have immense potential to personalize combination therapy for treating aggressive cancers, patients. RELEVANCE: Aggressive cancers are treated with, a combination of drugs, however not all patients and cancers respond to any one form of drug combination therapy. Effective combination therapy in the treatment of cancer will therefore require versatile drug delivery platforms capable of personalizing combination regimens for individual patients.